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Systemic JIA the Clinical Picture

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Systemic JIA the Clinical Picture

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Systemic JIA the Clinical Picture

  1. 1. Systemic JIA: The Clinical Picture Michal J Cidon MD Pediatric Rheumatology February 7, 2015
  2. 2. Systemic JIA • 1897 Sir Fredrick Still: 12 children with chronic arthritis, adenopathy, splenomegaly, fevers Variable Course: -12-40 % with monophasic course -5% have a polycyclic course -55% with persistent course High morbidity: short and long term (MAS, FTT, joint damage, amyloidosis) Poor prognostic indicators by 6 mo: persistent fever, steroid dependency, thrombocytosis, polyarthritis, hip disease, early joint damage, polymorphism of MIF gene Cassidy et al. Textbook of pediatric rheumatology. 6th ed., Philadelphia: Saunders Elsevier; 2011
  3. 3. Juvenile Rheumatoid Arthritis (ACR) Juvenile Chronic Arthritis (EULAR) Juvenile Idiopathic Arthritis (ILAR) Systemic Systemic Systemic Polyarticular Polyarticular (RF-) Polyarticular (RF-) JRA (poly, RF+) Polyarticular (RF+) Oligoarticular Pauciarticular Oligoarticular (persistent) Oligoarticular (extended) Juvenile psoriatic arthritis Psoriatic arthritis Juvenile ankylosing spondylitis Enthesitis related arthritis (ERA) Undifferentiated
  4. 4. S-JIA ILAR classification criteria 1. < 16yo 2. Fever ≥2 weeks, quotidian in pattern (≥39c once a day and return to ≤37c), documented daily for ≥3 days 3. Arthritis ≥1 joint ( for ≥6 weeks) 4. At least one of the following: evanescent erythematous rash generalized LND enlargement Hepatomegaly and/or splenomegaly; serositis Exclusions: 1.Psoriasis or a history of psoriasis in a patient or first degree relative 2. Arthritis in HLAB27 male > 6yo 3. AS, enthesitis-related arthritis, sacroiilitis with IBD, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders in a first degree relative ●
  5. 5. Systemic JIA ● Autoinflammatory syndrome -Usually lacks autoantibodies - No specific HLA, but association with HLA-DR and a novel genomic region on chromosome1 - No auto-reactive lymphocytes ● Disease driven cytokine dysregulation: -Proinflammatory cytokines (IL1, IL6, IL18) -Anti-inflammatory cytokine (IL-10) ● Promoter polymorphism (IL6 and TNFα)
  6. 6. Epidemiology • Prevalence 3.5/100,000 • Incidence (0.4-0.9 per 100,000/year) • 5-15% of JIA in North America and Europe • No gender difference • Equal age distribution vs. majority dx 0-5 yrs (74/136); peak at 2yo (17/136)* ● Variable ethnic composition *Behrens el al. J Rheum 2008; 35 (2): 343
  7. 7. S-JIA : Early Clinical Manifestations • Very ill: fatigue, anemia, fever, pain • Systemic features predominate early in the course and may overshadow or precede arthritis Feature Frequency Fever >98% Typical Rash 95% Arthritis >88% HSM 85% LAD 70% Pericarditis 35% Pleuritis 20% Abdominal pain 10%
  8. 8. SJIA Quotidian Fever Curve
  9. 9. Arthritis in S- JIA • Early symptom • Early affected joints: wrists, knees, ankles • Atypical joints (TMJ, cervical spine, hips) • Chronic progressive arthritis (1/3-1/2 pts) • Synovial cysts • Tenosynovitis
  10. 10. Rash in S-JIA ● Evanescent, salmon colored, migratory, fleeting, pruritic (5%) ● Worse with fever ● Biopsy: perivascular mononuclear cells and neutrophils ● Activated keratinocytes express S100 proteins MRP8 and MRP14 ● Leukocytes within epithelium of sweat gland ducts
  11. 11. S-JIA manifestations • LAD ( follicular hyperplasia) • Splenomegaly ( 50%) • Hepatic abnormalities (periportal infiltrates of inflammatory cells, hyperplasia of kupffer cells) • Serositis - Primarily pericarditis (early presentation, recurrent, rarely associated with myocarditis) -Asymptomatic pleuritis and pleural effusions ● Myositis ● Not associated with uveitis
  12. 12. Macrophage Activation Syndrome • Uninhibited production and activation of macrophage and T cells leading to a inflammatory multi-organ failure: - Liver dysfunction - CNS inflammation - Pancytopenia - Hyperferritinemia - Hemophagocytosis • Incidence of overt MAS (6.7-13%) with mortality rate of 8- 22% • Incidence “occult MAS” (30%) - CD163 staining in BM (Behrens et al, 2007) - sIL2R and sCD163(Bleesing et al, 2007)
  13. 13. MAS Diagnosis IL10 IFNγ Severe MAS Monogenic defect in cytotoxic granule exocytosis (FHL causative genes) OR HLH-2004 criteria ≥5/8 Clinical: Fever, Splenomegaly Labs:, Cytopenia>2 cell lines :Hb<9, Neutrophils<1000, Platelets<100 Ferritin>500mg/l Fibrinogen<150, Triglycerides>265mg/dl sCD25 ( soluble IL2 receptor)>2400U/ml, Low or absent NK cell activity, Hemophagocytosis in bone marrow, spleen or LNDS healthy Behrens, ACR 2014 Mild MAS
  14. 14. Cardiopulmonary complications Arthritis Care Res (Hoboken). 2013 May;65(5):745-52. doi: 10.1002/acr.21889. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Kimura Y el al. - Case of pulmonary interstitial and intra-alveolar cholesterol granulomas (Schultz R. et al, 2001) - Cross sectional study: restrictive pulmonary function (Van der Net J. el al,1997) - Case report of pulmonary hypertension (Padeh S. el al, 1991) - PFT abnormalities ( Wagener J. el al, 1981) - Interstitial pulmonary disease in 8/191 JRA pts ( Athreya el al, 1980)
  15. 15. S-JIA cases with pulmonary complications at Stanford Age of s- JIA dx Gender CP disease Time to CP Outcome Case1 13mo Male ILD 14months Stable Case 2 3yo Female PH/ vasculopathy 20 months Fatal Case 3 14yo Female PH/ILD? 46months Improved Case 4 17yo Female PH/ILD 17 months Fatal Case 5 17yo Female ILD 29months Improved Case 6 9 yo Female PH unclear improved
  16. 16. S-JIA Treatment Historically: NSAIDS, IVIG, corticosteroids, methotrexate, anti-TNF, cyclosporin, thalidomide, cyclophosphamide, autologous stem cell transplant Current: targeted biologic therapy : -anti-IL1: (Anakinra: IL1Ra, Rilonacept: IL1R-AcP, Canakinumab: mab IL1) ssCrontstein el al, 2013 Cronstein el al, 2013
  17. 17. S-JIA Treatment Current: targeted biologic therapy : -Anti-IL6 ( Tocilizumab) -Binds with IL-6 receptor on cell membranes or in soluble form -New recommended guidelines by the ACR ( 2013) -Consensus Treatment Plans ( CARRA, 2012): 4 arms: GC only, Methotrexate, Anakinra, Tocilizumab
  18. 18. Questions • What disease models can we use to learn about the predisposition to ILD in s-JIA? • Does ILD in s-JIA have unique pathophysiologic determinants? • What is the role of biologic medications in the development of ILD in s-JIA?
  19. 19. References 1.Behrens E.M., T. Beukelman, L. Gallo et al., “Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR),” Journal of Rheumatology, vol. 35, no. 2, pp. 343–348, 2008. 2. Beukelman T. Treatment advances in systemic juvenile idiopathic arthritis. F1000Prime Rep. 2014 Apr 1;6:21. 3.Bleesing J. el al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007 Mar;56(3):965-71. 4. Cassidy, J.T, and Petty, R.E el al. (Sixth Ed). (2010). Textbook of Pediatric Rheumatology. San Francisco, CA: Saunders. 5. Dewitt EM el al. Consensus treatment plans for new-onset systemic Juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012 Jul;64(7):1001-10. 6. Gurion R. el al. Systemic Arthritis in Children: A Review of Clinical Presentation and Treatment. Inte J Inflam. 2012; 2012:271569. 6.Kimura Y el al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2013 May; 65 (5): 745-52. 7. Petty RE, Southwood TR, Manners P et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.

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